Cholesterol is the most abundant sterol in animal tissues. It is the precursor of a number of other steroids, including several steroid hormones.
Cholesterol is the product of a complex enzymatic proces. Beta-hydroxy-beta-methylglutaryl CoA is reduced by beta-hydroxy-beta-methylglutaryl CoA (HMG-CoA) reductase to yield mevalonic acid. Mevalonic acid is converted into squalene. Squalene is attacked by molecular oxygen, yielding squalene 2,3-epoxide, and this is cyclized into lanosterol by squalene oxide cyclase (SOC). Finally, lanosterol is converted into cholesterol. Several of the foregoing conversions are multi-step processes, and alternative pathways exist.
Nelson, et al., JACS 100: 4900 (1978) reported that 4, 4,10 beta-trimethyl-trans-decal-3beta-ol (TMD) specifically inhibited cholesterol biosynthesis in both rat liver enzyme preparations and in CHO cells. After incubation with rat liver homogenate, 4,4,10beta-trimethyl-trans-decalin-3beta, 7beta-diol was isolated as the major product of TMD metabolism. They postulated that TMD inhibited the cyclization of squalene oxide. A limited investigation into structure-activity relationships (by preparation and testing of the 4alpha,10 beta-dimethyl and 10 beta-methyl analogues) led to the conclusion that the 4alpha-methyl group played a significant role in the inhibition. (See also Chang, et al., J. Biol. Chem., 254: 11258, 1979). Nelson considered the hypothesis that 1-TMD acts as an analogue of a transition state between squalene oxide and the cyclized product, but noted that the inhibitory activity of d-TMD was inconsistent with that speculation. TMD and its 4,10 beta-dimethyl analogue are both reported to be nonoompetitive inhibitors of SOC, and they both had virtually no effect on the cyclases of higher plants. Duriatti, et al., Biochem. Pharmacol., 34: 2765 (1985).
Cattel, et al., Lipids, 21: 31-38 (1986) suggested broadly that inhibitors of 2,3-oxide squalene cyclases might behave as very selective hypocholesterolemic drugs. They focused on the use of 2-aza-2-dihydrosqualene and its derivatives. They did not express any interest in substituted or in trans-decalols.